HIV-ASSOCIATED CNS DYSFUNCTION IN PEDIATRIC AIDS

  • Dickson, Dennis W (PI)
  • Lyman, William D. (PI)
  • Berman, Joan (PI)
  • Davies, Peter (PI)
  • Chiu, Fung-Chow (PI)
  • Lyman, William D. (PI)
  • Davies, Peter (PI)

Project: Research project

Description

The overall hypothesis to be tested in this proposal is that exposure of
the human fetal central nervous system (CNS) to HIV-1 may be sufficient to
cause the neurological dysfunction characteristic of pediatric AIDS. The
basis for this assumption is that a significant number of children with
AIDS and others without clinical signs of disease but with congenital HIV-1
infection exhibit cognitive, behavioral, and neurodevelopmental
abnormalities. Significant neuropathologic changes in the CNS of children
and fetuses infected by HIV-1 but without other signs of AIDS have also
been noted. Furthermore, HIV-1 nucleic acid sequences or proteins and
signs of productive viral infection have been observed in the affected
tissues and studies in vitro have demonstrated HIV-1 infection of glial
cells. To define the role of HIV-1 in pediatric AIDS more precisely, a
group of neuroscientists, each expert in a different neural cell type, has
come together to pursue this question using a combination of morphologic,
biochemical an molecular biologic techniques. Because of alterations in
normal cognitive development in HIV-1 infected children, Project 1 will
study the effect of HIV-1 on neuronal differentiation with a focus on
specific neurotransmitter systems and on neuronal cytoskeletal components.
Project 2 will complement Project 1 in that it will focus primarily on the
astrocyte cytoskeleton and metabolic function in HIV-1 infection because
of the reactive astrocytosis described in pediatric AIDS and the ability of
astrocytes to elicit cytokines which may modulate CNS function. Project 3
will focus on microglia in the fetal CNS because this cell type is believed
to be pivotal in AIDS neuropathology. This project will examine HIV-1
infection of microglia in vivo and in vitro and examine the role of
cytokines in tissue damage. Because myelin pathology is prominent in
pediatric AIDS, Project 4 will examine myelinogenesis and dysmyelination in
the human fetal CNS exposed to HIV-1 in vivo. Project will also
investigate the mechanisms related to myelin biology using dissociated cell
culture and organotypic explant cultures. Project 5 focuses on the
involvement of endothelial cells in the pathophysiology of CNS disease
because evidence indicates that endothelial cells may be infected by HIV-1
and they provide the first barrier to viral entry into the CNS.
Additionally, endothelial cells produce cytokines which may be involved in
the pathophysiology of AIDS. Lastly, Project 6 will use an in vitro
neuronal cell model to explore the interaction of HIV-1 genes on host cell
gene expression and converse, host cell control over HIV-1 gene expression.
The studies proposed in this Program Project application should answer many
of the pressing questions related to nervous system disease in pediatric
AIDS. Among these questions are the determination of a direct neurotropism
of HIV-1; factors that are involved in the neuroinvasiveness of this virus;
and, mechanisms of HIV neurovirulence. These studies may suggest new
strategies to prevent or treat more effectively neurologic disease in
pediatric AIDS.
StatusFinished
Effective start/end date9/30/904/30/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Microglia
Neuroglia
HIV-1
HIV
Cytokines
Astrocytes
Acquired Immunodeficiency Syndrome
Fetus
Pathology
Brain
Population
In Vitro Techniques

ASJC

  • Medicine(all)